The periosteum is now widely recognized as a homeostatic and therapeutic target for actions of sex steroids and intermittent parathyroid hormone (PTH) administration. Androgens and PTH stimulate while estrogens suppress periosteal expansion in a number of experimental models. However, low estrogen concentrations may also promote periosteal expansion by direct actions or indirectly by permitting the stimulatory effects of androgens or mechanical stimulation. The mechanisms by which sex steroids and PTH influence this key skeletal envelope are not known. We have found that sex steroids and PTH have common properties in protecting periosteal osteoblasts from apoptosis. In sharp contrast, estrogens as compared to androgens and PTH have opposing actions to regulate the recruitment of early periosteal osteoblast progenitors. The estrogen receptor (ER) itself has important actions both as a site for liganded estrogen interaction and as an independent modulator. The liganded ER attenuates periosteal osteoblast differentiation while in its unoccupied configuration, it potentiates periosteal osteoblast differentiation. We hypothesize that sex steroids and PTH promote the survival of mature periosteal osteoblasts. In parallel, estrogens suppress whereas androgens, intermittent PTH, and the unliganded ER promote periosteal expansion by exerting opposite actions on the proliferation and differentiation of early periosteal osteoblast progenitors. The effect of combined estrogen and PTH administration to the periosteal surface reflects the relative balance between prolongation of osteoblast survival, an action shared by both hormones, and opposing actions of PTH and estrogens on proliferation and differentiation of progenitor periosteal osteoblasts. To test these hypotheses, we will examine whether estrogens versus androgens, PTH and unliganded ER differentially regulate differentiation and proliferation of distinct populations of periosteal osteoblast precursors. The contribution of pro-differentiating versus anti-apoptotic actions of sex steroids, intermittent PTH and the combination of PTH and estrogens to the periosteal expansion that occurs with skeletal maturity will be investigated in vivo. Finally, we will establish in vivo that the osteoblast-specific actions of estrogens account for their effects on periosteal bone mass. Understanding the cellular and molecular mechanisms by which sex steroids and PTH act and interact to regulate periosteal preservation or expansion, could lead to new therapeutic approaches to the treatment of osteoporosis. PUBLIC HEALTH RELEVANCE: The periosteum is now widely recognized as a homeostatic and therapeutic target for actions of sex steroids and intermittent parathyroid hormone (PTH) administration. Androgens and PTH stimulate while estrogens suppress periosteal expansion in a number of experimental models. We hypothesize that sex steroids and PTH promote the survival of mature periosteal osteoblasts. In parallel, estrogens suppress whereas androgens, intermittent PTH, and the unliganded ER promote periosteal expansion by exerting opposite actions on the proliferation and differentiation of early periosteal osteoblast progenitors.